tbuckley/cabot-search huggingface dataset:
SHR-1701 plus chemotherapy as first-line treatment for unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC).
Authors: yi wang, Hong Liu, Qingwei Wang, Naian Qiao, Jianbo Wang, Bingxu Tan, Bo Cheng, Yunxia Chu, Huajun Li, Yufeng Cheng
Journal: Journal of Clinical Oncology (2023)

363 Background: Platinum-based chemotherapy is the standard first-line treatment for advanced or metastatic ESCC. Recently, the combination of PD-(L)1 pathway blockade with chemotherapy has shown synergistic efficacy in a few clinical trials. SHR-1701 is a novel bifunctional fusion protein composed of a mAb against PD-L1 fused with the extracellular domain of TGF-β receptor II. The purpose of this ongoing phase II trial (ChiCTR2000039909) was to evaluate the efficacy and safety of SHR-1701 combined with chemotherapy for unresectable locally advanced, recurrent or metastatic ESCC in China. Methods: This trial enrolled systemic treatment-naive patients(pts) with histologically or cytologically confirmed unresectable locally advanced, recurrent or metastatic ESCC who had ECOG PS of 0-1. Eligible pts received SHR-1701 (30mg/kg, iv, d1, q3w) combined with up to 6 cycles of albumin-bound paclitaxel (125mg/m2, iv, d1, d8, q3w) and cisplatin (75mg/m2, iv, d1, q3w). For those without progressive disease, maintenance treatment was administrated with SHR-1701 monotherapy until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression free survival (PFS), overall survival (OS), disease control rate (DCR), safety and biomarkers. Results: As of September 21, 2022, 18 pts were enrolled. The median age was 67.5 years (range: 46–75 years) and 16 (88.9%) were male. 10 of the pts (55.6%) presented with distant metastasis. 14 pts were included in the efficacy analysis and 17 were in the safety analysis. The ORR and DCR were 85.7% and 100.0%, respectively. One patient achieved a complete response (CR) which will reach confirmation at next visit. 11 pts had partial response (PR), including 9 confirmed PR, one pending confirmation PR, and one unconfirmed PR. In addition, one PR patient got a CR target lesion. Grade 3-4 treatment-related adverse events (AEs) were observed in 23.5% of pts, including neutropenia (11.8%), leukopenia (5.9%), anemia (5.9%), emesis (5.9%) and rash (5.9%). Immune-related AEs (irAEs) were observed in 52.9%, and only one grade 3 irAE of rash occurred. Conclusions: SHR-1701 plus chemotherapy showed potential clinical benefits with acceptable toxicity as first-line treatment, and it might be a favorable option for pts with advanced ESCC. Clinical trial information: ChiCTR2000039909 .
Impact of early-onset colorectal cancer on utilization of chemotherapy and outcomes in patients with stage II disease.
Authors: Jacob Beck Leary, Junxiao Hu, Sean Davis, Alexis Diane Leal, S. Lindsey Davis, Sunnie S. Kim, Robert William Lentz, Tyler Friedrich, Jon Vogel, Whitney Herter, Brandon C. Chapman, Wells A. Messersmith, Christopher Hanyoung Lieu
Journal: Journal of Clinical Oncology (2023)

85 Background: Rising rates of early-onset colorectal cancer (EOCRC) pose a dilemma for clinicians when deciding how to treat early-stage patients to maximize outcomes. While standard-of-care for Stage II colon cancer is largely surgical resection, evidence suggests that treatment selection may differ by patient age. We sought to determine whether rates of adjuvant chemotherapy administration differ between early and later-onset patients with Stage II CRC. Methods: Data were derived from the Flatiron National Database spanning 1/1/2003 to 8/1/2021. Patients 18 years or older with Stage II CRC were grouped into those aged 18-49 (EOCRC) and those aged 50 or older (LOCRC). Demographic characteristics, ECOG score, stage and site of tumor, and chemotherapy were included for all patients. Primary outcomes of interest included rates of adjuvant chemotherapy administration by age and ethnicity. Univariate and multivariable logistic regression models were used to evaluate relationships between chemotherapy administration, age groups, and ethnicity while adjusting for significant covariates. Results: Of 2133 patients with Stage II CRC, 1606 patients with complete data were included. A secondary analysis of 1065 patients with colon cancer was performed to address potential confounding factors related to neoadjuvant and/or adjuvant chemotherapy given in patients with stage II rectal cancer. Mean age of EOCRC patients was 45.0 years (range: 41.0-48.0) vs. 68.0 years (60.0-75.0) for LOCRC. Adjusting for ethnicity, gender, site, and ECOG score, multivariate analysis showed EOCRC patients received chemotherapy significantly more often than LOCRC patients for stage II CRC (adjusted odds ratio 1.85, 95% CI 1.32-2.60, p &lt; 0.001). Similar findings were observed in the colon cancer only cohort (adjusted OR 2.02, 95% CI 1.31-3.09, p &lt; 0.001). By ethnicity, non-Hispanic patients received chemotherapy at significantly lower rates than Hispanic patients in both cohorts (adjusted odds ratio 0.58, 95% CI 0.39-0.88, p = 0.009 and adjusted odds ratio 0.55, 95% CI 0.34-0.91, p = 0.018). In a subgroup analysis of Stage IIA patients, multivariate logistic regression adjusting for gender, ECOG, site, and ethnicity showed that patients with EOCRC were more likely to receive chemotherapy than patients with LOCRC (adjusted odds ratio 1.91, 95% CI 1.21-2.99, p = 0.005). Updated survival data will be presented. Conclusions: Adjuvant chemotherapy is given preferentially in Stage II EOCRC, even in Stage IIA disease, despite deviation from established guidelines. This may expose patients at low risk for recurrence to unnecessary toxicities and reveals potential provider bias in favor of younger patients in aggressively treating CRC, despite unclear evidence for any outcome benefit.
Biomarker analysis from a phase I/I1b study of regorafenib and nivolumab (rego/nivo) in microsatellite stable (MSS) colorectal cancer (CRC).
Authors: James Yu, Youngchul Kim, Rutika Mehta, Ruoyu Miao, Jonathan R. Strosberg, Iman Imanirad, Dae Won Kim, Richard D. Kim
Journal: Journal of Clinical Oncology (2023)

188 Background: Our previous phase I/Ib study revealed modest clinical efficacy of rego/nivo in refractory MSS-CRC, implying benefits in selected populations. This has prompted us to investigate predictive biomarkers. Methods: Pre-treatment tumor samples from the previous phase Ib rego/nivo study were obtained and assessed for mRNA sequencing (RNAseq). Response-associated transcripts were identified using DESeq2 method and annotated using gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis. Results: A total of 19 pretreatment tumor samples were analyzed including 14 patients (pts) with disease control (DC) (2 partial response and 12 stable disease) and 5 pts with progression disease (PD). We observed significant upregulation of 89 genes including SFTPB ( P&lt;0.001), SFTPA1 ( P&lt;0.001), ERICH6B ( P&lt;0.001) , XIST ( P&lt;0.001), IGHV2-26 ( P&lt;0.001), RETNLB ( P=0.005), VWA5B1 ( P=0.033), IGHV3-53 ( P&lt;0.001), POTEH ( P=0.015), IGHV1-3 ( P=0.001) and downregulation of 70 genes including AFAP1-AS1 ( P=0.022), PRSS21( P&lt;0.001), NTSR1 ( P&lt;0.001), CALB1 ( P=0.033), FAM83A ( P=0.013), TBL1Y ( P=0.045), WNT7A ( P=0.022), PADI1 ( P&lt;0.001), KRT6A ( P=0.030), KRT17 ( P=0.002) on RNA sequencing in the DC compared to PD. GO pathway enrichment analyses revealed 44 significantly upregulated pathways including positive regulation of B cell activation ( P&lt;0.001), B cell receptor signaling pathway ( P&lt;0.001), Phagocytosis engulfment ( P&lt;0.001), Fc-gamma receptor signaling pathway involved in phagocytosis ( P&lt;0.001), endocytosis ( P&lt;0.001), immunoglobulin receptor binding ( P&lt;0.001), serine-type endopeptidase activity ( P&lt;0.001) in the DC compared with PD group. Nine downregulated pathways including cell-substrate junction assembly ( P&lt;0.001), extracellular matrix (ECM) organization ( P=0.030), and ephrin receptor activity ( P=0.046) were observed in the DC compared with PD. KEGG pathway enrichment analysis revealed 8 significantly downregulated pathways including PI3K-Akt signaling ( P=0.009), ECM-receptor interaction ( P=0.006), Focal adhesion ( P=0.028), and Glycine, serine and threonine metabolism ( P=0.007) pathways in the DC compared with PD. Conclusions: RNAseq and following gene set enrichment analysis between pts with DC and PD revealed several dysregulated pathways involving immune regulation including macrophage and B cell activation, and also PI3-Akt signaling, ECM organization/receptor interaction, and adhesion, which are consistent with previous translational studies in other solid tumors. These dysregulated genes and pathways related to differentially expressed genes may need to be further evaluated as potential predictive biomarkers for rego/nivo or other tyrosine kinase inhibitor plus PD-1 blockade in MSS-CRC.
ctDNA-based fusion detection for advanced colorectal cancer with a partner-agnostic assay.
Authors: Reagan Barnett, Sante Gnerre, Jason Willis, Michael J. Overman, Kanwal Pratap Singh Raghav, Christine Megerdichian Parseghian, Arvind Dasari, Maria Pia Morelli, Benny Johnson, Madhulika Eluri, Leylah Drusbosky, Scott Kopetz, Van K. Morris
Journal: Journal of Clinical Oncology (2023)

186 Background: Actionable mutations can predict therapeutic benefit in patients with advanced malignancies, though clinical relevance of fusion testing for advanced colorectal cancer (aCRC) remains undefined. Identification of fusions from circulating tumor DNA (ctDNA) has previously been restricted to defined oncogenic fusion partners. To improve the sensitivity for fusion detection, we evaluated a partner-agnostic fusion analysis from ctDNA of patients with aCRC. Methods: De-identified data from Guardant Health was reviewed for 18,558 patients with aCRC who underwent ctDNA NGS testing by Guardant360 (Redwood City, CA) between 2017-2022. Fusion results were analyzed with a partner-agnostic bioinformatic approach. A fusion was defined as “clonal” if the variant allele frequency (VAF) ratio exceed ≥50% of highest somatic VAF, and “subclonal” if &lt; 50% maxVAF. Microsatellite instability (MSI) status [MSI-high (bMSI-H) or microsatellite stable (bMSS)] and anti-EGFR exposure signature were determined using prior methods. Associations between fusion occurrence and coexisting alterations were performed using Fisher’s exact test. Results: Fusions were detected in 221 (1.2%) of patients with aCRC. 258 activating fusions were detected in 187 patients; FGFR3 (N = 59, 23%), RET N = 55, 21%), BRAF (N = 43, 17%), and ALK (N = 41, 16%) were most frequent. There were 71 previously unreported fusions in 28 additional patients; RET (N = 16; 23%), MET (N = 15, 21%), and BRAF (N = 11; 15%) were most prevalent. Clonal fusions occurred in 7% (18/258) of all activating fusions; RET (5/18, 28%) and FGFR3 (3/18, 17%) were most common and associated with bMSI-H status relative to bMSS (27% vs 4%, OR 8.165, 95% CI 2.332-33.99; p = 0.0076). Clonal fusions occurred less commonly in samples with a prior EGFR signature (OR 0.22, 95% CI 0.05-0.997, p = 0.049). Most detected fusions were subclonal including ALK, FGFR1-3, MET, RET and ROS1. Conclusions: Highly specific partner-agnostic fusion detection is feasible to increase sensitivity of ctDNA assay performance. Oncogenic fusions occurred in ~1% of all patients with aCRC. Clonal fusions as oncogenic drivers were infrequent and associated with bMSI-H status. Subclonal fusions were more common and occur in a setting consistent with prior exposure to anti-EGFR therapies. Reporting fusion partners and clonality from ctDNA may guide oncologists on the appropriate context for consideration of fusion-directed treatments.
Efficacy and safety of tislelizumab plus cetuximab and irinotecan in patients with previously treated RAS wild-type advanced colorectal cancer: A phase II, single-arm study.
Authors: Xiaojing Xu, Yiyi Yu, Yan Wang, Yuehong Cui, Wei Li, Li Liang, Qian Li, Shan Yu, Yi Feng, Qing Liu, Pengfei Zhang, Minzhi Lv, Tianshu Liu
Journal: Journal of Clinical Oncology (2023)

125 Background: For adequately treated patients (pts) with advanced colorectal cancer, the current third-line treatment standard of TKIs or TAS-102 administration has a low clinical objective response rate and its effectiveness seems to be limited. Preclinical studies have suggested that EGFR pathway blockage and immune checkpoint inhibition have synergistic therapeutic effects in these pts. The purpose of this study was to examine the efficacy and safety of tislelizumab (anti-PD-1 antibody) plus cetuximab and irinotecan in pts with previously treated RAS wild-type advanced colorectal cancer. Methods: This is an open-label, single-arm, phase II study. RAS wild-type advanced colorectal cancer pts with at least two previous lines of therapy were included in this study and administered with tislelizumab plus cetuximab and irinotecan until disease progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) (RESCIT 1.1). Secondary endpoints included DCR, PFS, OS and safety. Results: In total, 35 eligible RAS wild-type advanced colorectal cancer pts were enrolled from March 2021 to September 2021. The median age was 58 years. All 35 pts were identified as BRAF/RAS wild-type, and 33 (94%) had left-sided colon cancer. The percentages of pts with second-line, third-line and ≥fourth-line previous treatments were 37%, 49%, and 14%, respectively. Thirty-four pts (97%) had received targeted therapies previously, including 29 (83%) with anti-EGFR therapy. By Aug 17th, 2022, 2 pts had withdrawn from the study for personal reasons, and the remaining 33 pts were evaluated for efficacy. Twelve of the 33 (36.4%) pts achieved clinical partial remission and 14 (42.4%) achieved stable disease; disease progression occurred in 6 pts and 1 patient died. The unconfirmed ORR was 36.4% and the DCR was 78.8%. The confirmed ORR was 33.3%. Until Aug 17th, 2022, 1 pts continued treatments. The median PFS was 6.83 months. Among the 33 treated pts, 32 (97.0%) had treatment-related adverse events (AEs). Common AEs included rash (n=32), fatigue (n=30), decreased appetite (n=30), nausea (n=28), diarrhea (n=16), vomiting (n=14), liver dysfunction (n=13), leukopenia (n=12) anemia(n=10), neutropenia (n=9), paronychia (n=8), oral mucositis (n=4), and thrombocytopenia (n=4). Three (9.1%) of the 33 pts reported grade ≥3 AEs, including rash (n=1), neutropenia (n=2). Conclusions: Tislelizumab plus cetuximab and irinotecan showed an encouraging clinical efficacy and tolerable safety in previously treated pts with RAS wild-type advanced colorectal cancer. Clinical trial information: NCT05143099 .
First-line of camrelizumab plus pyrotinib and chemotherapy in HER2-positive advanced gastric or gastroesophageal junction adenocarcinoma: A dose escalation and expansion phase I study.
Authors: Liangjun Zhu, Sheng Li, Jun Bao, Xiaoyou Li, Quanliang Yang, Junying Xu, Surong Chen, Ge Feng, Chao Gao, Lin Feng, Bin Lu, Min Miao, Xinchu Ni, Guofang Wang, Lei Yang
Journal: Journal of Clinical Oncology (2023)

356 Background: The combination of PD-1 and HER2 blockades showed potential benefit for patients with HER2-positive gastric cancer. This study aimed to investigate the safety and efficacy of camrelizumab plus pyrotinib and chemotherapy in the first-line setting for HER2-positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. Methods: This phase I, open-label, clinical trial (ChiCTR2000029717) included dose-escalation and dose-expansion cohorts. Patients aged 18 or older with HER2-positive G/GEJ cancer were enrolled. In dose-escalation phase, patients were administrated with three-week cycle of oral pyrotinib 240mg, 320mg or 400mg daily, intravenous camrelizumab 200mg and oxaliplatin 130mg/m 2 on day 1, and oral capecitabine 1000mg/m 2 twice a day for two weeks followed by one week off until unacceptable toxicities, progressive disease or death. Additional patients were enrolled in a dose-expansion phase and received maximum tolerated dose determined in the dose-escalation cohort. The primary endpoints were the safety and objective response rate (Response Evaluation Criteria in Solid Tumors version 1.1). Results: Between June, 2020 and June, 2022, a total of 31 patients were enrolled, with 9 patients in the dose-escalation phase (three patients received pyrotinib 240mg, 320mg or 400mg each) and 22 in the dose-expansion phase. During dose-escalation, five patients experienced six dose-limiting toxicity, including diarrhea (n=4), vomiting (n=1) and decreased appetite (n=1). The maximum tolerated dose of pyrotinib was 320 mg, which was chosen for dose-expansion. For 25 patients received pyrotinib 320 mg, 13 (52.0%) developed grade 3 or higher adverse events (AEs), and 6 (24.0%) discontinued treatment due to AE. The most common AE of any grade was diarrhea (96.0%), followed by vomiting (60.0%), decreased appetite (56.0%) and anemia (56.0%). The objective response rate and disease control rate were 96.0% and 100%, respectively. The 12-month progression-free survival rate and overall survival rate were 77.1% and 89.3%, respectively. Conclusions: Camrelizumab plus pyrotinib and chemotherapy showed promising efficacy in the first-line treatment of HER2-positive G/GEJ cancer, with acceptable safety profiles. The study is ongoing. Clinical trial information: ChiCTR2000029717 .[Table: see text]
SOX plus bevacizumab versus SOX plus cetuximab as initial treatment of recurrent advanced colorectal cancer with wild-type KRAS (MCSGO-1107 study): A phase II randomized study.
Authors: Shu Okamura, Yujiro Nishizawa, Yoshinori Kagawa, Mitsunobu Imasato, Masakazu Miyake, Nobuyoshi Ohara, Yoshihito Ide, Ryoji Nonaka, Koki Tamai, Ken Konishi, Takeshi Kato, Genta Sawada, Mitsuyoshi Tei, Taroh Satoh, Norikatsu Miyoshi, Mamoru Uemura, Hidekazu Takahashi, Kohei Murata, Yuichiro Doki, Hidetoshi Eguchi
Journal: Journal of Clinical Oncology (2023)

136 Background: Although clinical outcomes of chemotherapy in patients with locally advanced or metastatic colorectal cancer (CRC) have improved over the last decade, the standard-of-care chemotherapy regimens for patients with unresectable RAS wild-type CRC remain to be discussed. The aim of this study was to compare S-1 and oxaliplatin (SOX) + bevacizumab (B-mab) with SOX + cetuximab (C-mab) in patients with previously untreated, unresectable, locally advanced, or metastatic CRC with wild-type KRAS. Methods: This phase II, randomized, open-label, multicenter study compared the efficacy and safety of SOX+B-mab with SOX+C-mab in patients with previously untreated, unresectable, locally advanced, or metastatic CRC with wild-type KRAS. Forty-five patients were enrolled in this study between February 2012 and October 2016. Results: The overall response rate (ORR) for the SOX+B-mab group was 59.1%, whereas that for the SOX+C-mab group was 43.5% (p = 0.29). The disease control rate (DCR) for the SOX+B-mab group was 90.9%, whereas that of the SOX+C-mab group was 91.3% (p = 0.96). For all patients, median OS were 25.3 months (95% CI: 16.5–39.4 months) in the SOX+B-mab group and 15.5 months (95% CI: 7.30–30.4 months, p = 0.167) in the SOX+C-mab group. Median PFS were 11.7 months (95% CI: 7.37–18.2 months) in the SOX+B-mab group and 5.5 months (95% CI: 3.36–10.1 months, p = 0.077) in the SOX+C-mab group. In the SOX+B-mab group, OS and PFS were not significantly different with and without early tumor shrinkage (ETS). However, in the SOX+C-mab group, patients with ETS had significantly better OS (30.4 months [95% CI: 8.0–44.3 months, p = 0.032]) and PFS (12.0 months [95% CI: 5.1–19.7 months, p = 0.003]) than those without ETS. Conclusions: The safety and efficacy of SOX+B-mab and SOX+C-mab as initial treatment for unresectable CRC with wild-type KRAS were almost the same. ETS was more correlated with PFS in the SOX+C-mab group than in the SOX+B-mab group, suggesting consideration of treatment strategy based on ETS may improve patient prognosis, especially in patients receiving the SOX+C-mab regimen. Clinical trial information: UMIN000006706 .
Updated results from ALTER-C001 study: Efficacy and safety of anlotinib plus XELOX regimen as first-line treatment followed by maintenance monotherapy of anlotinib for patients with mCRC.
Authors: Jin Yan, Yunwei Han, Li Zhang, Yongdong Jin, Hao Sun
Journal: Journal of Clinical Oncology (2023)

137 Background: The standard first-line therapy followed by maintenance treatment is an optional approach to balance the efficacy and toxicity for metastatic colorectal cancer (mCRC). In general, this approach had been seen PFS benefit in some trials, but probably lack of OS benefit, which indicating that new regimens needed to be explored. Anlotinib, a novel multi-targeted TKI, significantly prolonged the PFS of refractory mCRC in a phase III clinical trial (NCT02332499). Previous results of this study exhibited antitumor efficacy and manageable toxicity for mCRC. Here we report an update results with a longer follow up. Methods: 29 patients with unresectable mCRC, aged 18-75, without prior systemic treatment and ECOG performance status 0-1 would be prospectively included. Anlotinib 10mg and capecitabine 1000mg/m 2 was given orally for 14 days in 3-week cycles; oxaliplatin 130mg/m 2 was given by intravenous infusion on day 1 in 3-week cycles. After 6 cycles of induction therapy, patients would receive anlotinib (12mg, po, d1~14, q3w) until disease progression or intolerable adverse events. The primary endpoint was PFS. Secondary endpoints included ORR, DCR, DOR and safety. Results: At data cut-off date (June 30, 2022), a total of 31 patients were enrolled, the median age was 57 years, 23 (74%) were males, ECOG PS 0/1 was 18 (58%)/13 (42%), 28 (90%) had more than one metastatic tumor. Among them, 24 patients were available for efficacy assessment. The median PFS was 8.28 months (95% CI: 6.29-10.27) and the median DOR was 6.01 months (95% CI: 4.59-7.43). The ORR was 62.5% (95% CI: 40.6-81.2) and DCR was 91.7% (95% CI: 73.0-99.0) in best overall response assessment, of which the longest duration of treatment was 17.5 months. The treatment-related adverse events (TRAEs) occurred in 31 pts (100.0%) including nausea (58.1%), vomiting (51.6%), neutropenia (51.6%), leukopenia (35.5%), hypertension (35.5%). The Grade 3/4 TRAEs were neutropenia (12.9%), hypertension (12.9%), lipase elevated (9.7%), hypertriglyceridemia (6.5%), and leukopenia (3.2%). Conclusions: The updated results suggested that anlotinib combined with XELOX as first line regimen followed by anlotinib monotherapy as maintenance therapy showed a promising clinical benefit and favorable safety profile for mCRC, and the results needed to be confirmed in trials continued subsequently. Clinical trial information: ChiCTR1900028417 .